The present invention relates to a novel 2-aminopyridine compound, a process for producing it, and use thereof as a medicament.
Adenosine is an important regulatory factor involved in various intracellular metabolisms such as regulation of energy levels and cAMP levels in the living body, opening and closing calcium channels, and inflow of calcium ions into cells, and can exhibit its physiological activity by interaction with G protein-conjugated receptors on the surface of a cell. Adenosine receptors were at first classified into 2 classes, that is, A1 receptor and A2 receptor on the basis of their participation in adenylate cyclase (J. Neurochem., 33, 999-1003 (1979)), and thereafter, the A2 receptor was classified into 2 subtypes, that is, A2A and A2B on the basis of their affinity for NECA and CGS-21680 (Mol. Pharmacol., 29, 331-346 (1986); J. Neurochem., 55, 1763-1771 (1990)) which are adenosine A2 receptor agonists. Thus, 4 receptor subtypes, A1, A2 (A2A, A2B) and A3, have been identified until now. The A1 receptor is a protein conjugated with Gi/o family protein. By binding of ligands, it inhibits adenylate cyclase to suppress cAMP levels and activates phospholipase C (PLC) to promote production of inositol-1,4,5-triphosphate (IP3) and release of intracellular calcium ions. It is known that similar to the A1 receptor, the A3 receptor is a receptor suppressing cAMP levels and activating PLC to promote production of IP3 and release of intracellular calcium ions. On the other hand, the A2A and A2B receptors are those activating adenylate cyclase and promoting production of cAMP levels. It is also reported that A2B is conjugated with PLC via Gq/G11 protein, and promotes production of IP3 levels and inflow of calcium ions into cells (din. Invest., 96, 1979-1986 (1995)). These subtypes are different from one another in their distribution in tissues; that is, the A1 receptor occurs relatively abundantly in the heart, aorta, bladder, etc., the A2A receptor in the eyeballs, skeletal muscles, etc., and the A3 receptor in the spleen, uterus, prostate, etc., while the A2B receptor occurs relatively abundantly in proximity to the large intestine and in the eyeballs, lung, uterus and bladder (Br. J. Pharmacol., 118, 1461-1468 (1996)). The reason that adenosine receptor subtypes can exhibit their inherent functions is attributable to a difference in their distribution in tissues, a difference in topical adenosine levels and a difference in affinity of each subtype for ligands. Adenosine is involved in various physiological functions such as platelet agglutination, heartbeats, contraction of smooth muscles, inflammations, release of neurotransmitters, neurotransmission, release of hormones, cellular differentiation, growth of cells, death of cells, biosynthesis of DNA, etc., thus suggesting the relationship of adenosine with diseases in the neutral nerves, cardiovascular diseases, inflammatory diseases, diseases in the respiratory organs, immune diseases, etc., so usefulness of adenosine receptor agonists/antagonists against these diseases is expected. On one hand, important reports have been made in recent years on the relationship between the adenosine A2 receptor and the intestinal tracts. For example, it is reported that a relaxing action on colon longitudinal muscles is mediated by A2 receptor (Naunyn-Schmiedeberg""s Arch. Pharmacol., 359, 140-146 (1999)), and that the relaxing action of adenosine on contraction of guinea pig distant colon longitudinal muscles is mediated by A1 receptor and A2b receptor in longitudinal muscles (Br. J. Pharmacol., 129, 871-876 (2000)). Heretofore, antagonists for adenosine receptors, particularly for adenosine A2 receptor, have been noted to be useful as an agent for treating or preventing diabetes, diabetic complications, diabetic retinopathy, obesity or asthma, and expected to be useful as a hypoglycemic agent, an improving agent for impaired glucose tolerance, a potentiating agent for insulin sensitivity, a hypotensive agent, a diuretic, a therapeutic agent for osteoporosis, an anti-Parkinson""s disease agent, an anti-Alzheimer""s disease agent, a therapeutic agent for inflammatory intestinal diseases or a therapeutic agent for Crohn""s disease, etc.
For example, there are following reports on compounds having an antagonistic action particularly on A2B receptor.
(1) Compounds represented by the formulae: 
2,4-Dioxobenzo [g]pteridine
(2) Purine derivatives represented by the formula: 
(wherein R1 means (1) the formula 
(wherein X means hydrogen atom, hydroxyl group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group etc.; and R5 and R6 are the same as or different from each other and each means hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted saturated or unsaturated C3-8 cycloalkyl group etc.) or (2) a 5- to 6-membered aromatic ring which may have a substituent group and a hetero atom; W means the formula xe2x80x94CH2CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94; R2 means an amino group which may be substituted with an optionally substituted lower alkyl group etc., etc.; R3 means an optionally substituted C3-8 cycloalkyl group, an optionally substituted aryl group, etc.; and R4 means an optionally substituted lower alkyl group etc.), or a pharmacologically acceptable salt thereof or a hydrate of them (JP-A 11-263789).
(3) Purine derivatives represented by the formula: 
(wherein R1 represents hydrogen atom, hydroxyl group, a halogen atom, an optionally substituted C1-8 alkyl group, etc.; R2 represents an amino group which may be substituted with a C1-8 alkyl group, etc.; R3 represents a C3-8 alkynyl group which may be substituted with a halogen atom, hydroxyl group or a C1-4 alkyl group, etc.; Ar represents an optionally substituted aryl group, an optionally substituted heteroaryl group, etc.; and Q and W are the same as or different from each other and each represents N or CH), a pharmacologically acceptable salt thereof or a hydrate of them.
(4) A2B receptor antagonists described in Drug Development Research, 48: 95-103 (1999) and J. Med. Chem., 43: 1165-1172 (2000).
On one hand, as pyridine compounds, for example, there are reports relating to 5,6-aromatic substituted pyridine compound in WO 96/24584, U.S. Pat. No. 5,686,470 and U.S. Pat. No. 5,916,905. Further, in DE-A1 4117802, there are reports relating to 2-amino-3-pyridinecarbonitrile, and relating to the compound in which the 4-, 5- and 6-positions of the pyridine ring are substituted with phenyl groups. However, the relationship of these compounds with an adenosine receptor is not described or suggested, and is not known at all.
As described above, those compounds having an antagonism to an adenosine receptor, particularly an antagonism to an adenosine A2 receptor (especially A2b receptor), are expected to exhibit an excellent action as pharmaceutical preparations and desired to be provided. However, those compounds having an excellent antagonism to an adenosine receptor and also acting effectively as a medicament have never been found. Accordingly, the object of the present invention is to search for, and find, the receptor inhibiting compound which is useful as an agent for treating or preventing a disease to which an adenosine receptor (particularly A2 receptor, A2b receptor) relates.
Considering the above-described circumstances, the present inventors made intensive study. As a result, they have succeeded for the first time in synthesizing a compound represented by the formula: 
(wherein R1 represents cyano group, carboxyl group or an optionally substituted carbamoyl group; R2 represents hydrogen atom, hydroxyl group, an optionally substituted C1-6 alkoxy group, an optionally substituted C6-14 aromatic hydrocarbon cyclic group or an optionally substituted 5- to 14-membered aromatic heterocyclic group; and R3 and R4 are the same as or different from each other and each represents a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C6-14 aromatic hydrocarbon cyclic group, a 5- to 14-membered non-aromatic heterocyclic group or a 5- to 14-membered aromatic heterocyclic group which may have a substituent group, respectively, provided that the cases where (1) R1 is cyano group, R2 is 4-bromo-2-thienyl group, R3 is 3,4-dimethoxyphenyl group and R4 is 2-thienyl group, (2) R1 is cyano group, R2 is hydrogen atom, and each of R3 and R4 is phenyl group, (3) R1 is cyano group, R2 is 4-chlorophenyl group, R3 is phenyl group and R4 is 4-(3,4-dichlorophenyl)-1-oxo-2(1H)-phthalazinyl group, (4) R1 is cyano group, R2 is hydrogen atom, R3 is 4-pyridyl group and R4 is 1-piperazinyl group, (5) R1 is cyano group, R2 is hydrogen atom, R3 is 4-pyridyl group and R4 is a 1-pyridyl group, (6) R1 is cyano group, R2 is hydrogen atom, R3 is 4-pyridyl group and R4 is 4-diphenylmethyl-1-piperazinyl group, (7) R1 is cyano group, R2 is hydrogen atom, R3 is 4-pyridyl group and R4 is 4-morpholinyl group, (8) R1 is cyano group, R2 is 4-methylphenyl group, and each of R3 and R4 is phenyl group and (9) R1is cyano group, and each of R2, R3 and R4 is phenyl group are excluded) or a salt thereof, and they unexpectedly found that the compound and a salt thereof have an excellent antagonistic action on adenosine A2 receptor, particularly A2B receptor. As a result of further intensive study, they found that the compound or a salt thereof is useful not only as an agent for treating, preventing or improving a disease to which an adenosine receptor, particularly A2 receptor, especially A2B receptor, relates, for example, constipation, irritable bowel syndrome, constipation accompanying irritable bowel syndrome, organic constipation, constipation accompanying enteroparalytic ileus, constipation accompanying congenital digestive tract dysfunction, constipation accompanying ileus, diabetes, diabetic complications, diabetic retinopathy, obesity, asthma etc., but also useful as a hypoglycemic agent, an improving agent for impaired glucose tolerance, a potentiating agent for insulin sensitivity, hypotensive agent, a diuretic, a therapeutic agent for osteoporosis, an anti-Parkinson""s disease agent, an anti-Alzheimer""s disease agent, a therapeutic agent for inflammatory intestinal diseases, a therapeutic agent for Crohn""s disease etc., and thus completed the present invention.
That is, the present invention relates to (1) a compound represented by the above formula (I) or a salt thereof; (2) the compound according to the above-mentioned (1) or a salt thereof, in which R1 is cyano group; (3) the compound according to the above-mentioned (1) or a salt thereof, in which R1 is a carbamoyl group represented by the formula: 
(wherein R5 and R6 are the same as or different from each other and each represents hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C6-14 aromatic hydrocarbon cyclic group or an optionally substituted 5- to 14-membered aromatic heterocyclic group); (4) the compound according to the above-mentioned (1) or a salt thereof, in which R2 is a C6-14 aromatic hydrocarbon cyclic group or 5- to 14-membered aromatic heterocyclic group, each of which may have a substituent group; (5) the compound according to the above-mentioned (1) or a salt thereof, in which R2 is a phenyl group, naphthyl group, pyridyl group, thienyl group or furyl group, each of which may have a substituent group; (6) the compound according to the above-mentioned (1) or a salt thereof, in which R2 is a phenyl group which may be substituted with a halogen atom; (7) the compound according to the above-mentioned (1) or a salt thereof, in which R2 is hydrogen atom; (8) the compound according to the above-mentioned (1) or a salt thereof, in which R3 and R4 are the same as or different from each other and each represents a C6-14 aromatic hydrocarbon cyclic group or a 5- to 14-membered aromatic heterocyclic group, each of which may have a substituent group; (9) the compound according to the above-mentioned (1) or a salt thereof, in which R3 and R4 are the same as or different from each other and each represents a phenyl group, pyrrolyl group, pyridinyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, thienyl group, thiazolyl group, furyl group, naphthyl group, quinolinyl group, isoquinolinyl group, phthalazinyl group, naphthyridinyl group, indolyl group or isoindolyl group, each of which may have a substituent group; (10) the compound according to the above-mentioned (1) or a salt thereof, in which each of R3 and R4 represents a phenyl group, pyridyl group, thienyl group or furyl group which may have a substituent group, respectively; (11) the compound according to the above-mentioned (1) or salts thereof, wherein R3 and/or R4 represent a 5- to 14-membered non-aromatic heterocyclic group, a C6-14 aromatic hydrocarbon cyclic group or a 5- to 14-membered aromatic heterocyclic group, each of which may be substituted with at least one group selected from the following substituent group a (the above-mentioned xe2x80x9csubstituent group axe2x80x9d is a group consisting of (1) a hydroxyl group, (2) a halogen atom, (3) a nitrile group, (4) a nitro group, (5) a C1-6 alkyl group, C2-6 alkenyl group or C2-6 alkynyl group, each of which may be substituted with at least one group selected from (i) hydroxyl group, (ii) nitrile group, (iii) halogen atom, (iv) C1-6 alkylamino group, (v) di(C1-6 alkyl)amino group, (vi) C2-6 alkenylamino group, (vii) di(C2-6 alkenyl)amino group, (viii) C2-6 alkynylamino group, (ix) di(C2-6 alkynyl)amino group, (x) Nxe2x80x94C1-6 alkyl-Nxe2x80x94C2-6 alkenylamino group, (xi) Nxe2x80x94C1-6 alkyl-Nxe2x80x94C2-6 alkynylamino group, (xii) Nxe2x80x94C2-6 alkenyl-Nxe2x80x94C2-6 alkynylamino group, (xiii) aralkyloxy group, (xiv) TBDMS oxy group, (xv) C1-6 alkylsulfonylamino group, (xvi) C1-6 alkylcarbonyloxy group, (xvii) C2-6 alkenylcarbonyloxy group, (xviii) C2-6 alkynylcarbonyloxy group, (xix) Nxe2x80x94C1-6 alkylcarbamoyl group, (xx) Nxe2x80x94C2-6 alkenylcarbamoyl group and (xxi) Nxe2x80x94C1-6 alkynylcarbamoyl group, (6) a C1-6 alkoxy group, C2-6 alkenyloxy group or C2-6 alkynyloxy group, each of which may be substituted with at least one group selected from (i) C1-6 alkylamino group, (ii) aralkyloxy group and (iii) hydroxyl group, (7) a C1-6 alkylthio group, C2-6 alkenylthio group or C2-6 alkynylthio group, each of which may be substituted with at least one group selected from (i) hydroxyl group, (ii) nitrile group, (iii) halogen atom, (iv) C1-6 alkylamino group, (v) aralkyloxy group, (vi) TBDMS oxy group, (vii) C1-6 alkylsulfonylamino group, (viii) C1-6 alkylcarbonyloxy group and (ix) C1-6 alkylcarbamoyl group, (8) a carbonyl group substituted with a group selected from (i) C1-6 alkoxy group, (ii) amino group, (iii) C1-6 alkylamino group, (iv) di(C1-6 alkyl)amino group, (v) C2-6 alkenylamino group, (vi) di (C2-6 alkenyl)amino group, (vii) C2-6 alkynylamino group, (vii) di(C2-6 alkynyl)amino group, (viii) Nxe2x80x94C1-6 alkyl-Nxe2x80x94C2-6 alkenylamino group, (ix) Nxe2x80x94C1-6 alkyl-Nxe2x80x94C2-6 alkynylamino group and (x) Nxe2x80x94C2-6 alkenyl-Nxe2x80x94C2-6 alkynylamino group, (9) an amino group which may be substituted with one or two groups selected from (i) C1-6 alkyl group, (ii) C2-6 alkenyl group, (iii) C2-6 alkynyl group, (iv) C1-6 alkylsulfonyl group, (v) C2-6 alkenylsulfonyl group, (vi) C2-6 alkynylsulfonyl group, (vii) C1-6 alkylcarbonyl group, (viii) C2-6 alkenylcarbonyl group and (ix) C2-6 alkynylcarbonyl group, (10) a C1-6 alkylsulfonyl group, (11) a C2-6 alkenylsulfonyl group, (12) a C2-6 alkynylsulfonyl group, (13) a C1-6 alkylsulfinyl group, (14) a C2-6 alkenylsulfinyl group, (15) a C2-6 alkynylsulfinyl group, (16) a formyl group, (17) a C3-8 cycloalkyl group or C3-8 cycloalkenyl group, each of which may be substituted with at least one group selected from (i) hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) C1-6 alkyl group, (v) C1-6 alkoxy group, (vi) C1-6 alkoxy-C1-6 alkyl group and (vii) aralkyl group, (18) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with at least one group selected from (i) hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) C1-6 alkyl group, (v) C1-6 alkoxy group, (vi) C1-6 alkoxy-C1-6 alkyl group and (vii) aralkyl group, (19) a C6-14 aromatic hydrocarbon cyclic group which may be substituted with at least one group selected from (i) hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) C1-6 alkyl group, (v) C1-6 alkoxy group, (vi) C1-6 alkoxy-C1-6 alkyl group and (vii) aralkyl group, and (20) a 5- to 14-membered aromatic heterocyclic group which may be substituted with at least one group selected from (i) hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) C1-6 alkyl group, (v) C1-6 alkoxy group, (vi) C1-6 alkoxy-C1-6 alkyl group and (vii) aralkyl group); (12) the compound according to the above-mentioned (1) or a salt thereof, in which R3 and/or R4 represent a phenyl group, pyridyl group, thienyl group or furyl group, each of which may be substituted with at least one group selected from hydroxyl group, a halogen atom, a C1-6 alkyl group and a C1-6 alkoxy group; (13) the compound according to the above-mentioned (1) or a salt thereof, in which R3 or R4 is a 6-oxo-1,6-dihydropyridyl group which may have a substituent group; (14) the compound according to the above-mentioned (1) represented by the formula: 
(wherein R1 represents cyano group, carboxyl group or an optionally substituted carbamoyl group; R2 represents hydrogen atom, hydroxyl group, an optionally substituted C1-6 alkoxy group, an optionally substituted C1-6 alkylthio group, an optionally substituted C6-14 aromatic hydrocarbon cyclic group or an optionally substituted 5- to 14-membered aromatic heterocyclic group; R7 represents a group selected from the following substituent group b; R8 represents a C6-14 aromatic hydrocarbon cyclic group or a 5- to 14-membered aromatic heterocyclic group which may have a substituent group, respectively; and ring A represents a nitrogen-containing 6-membered ring which may be substituted with 1 to 4 groups selected from the following substituent group b.
 less than substituent group b greater than  a group consisting of hydrogen atom, a halogen atom, hydroxyl group, nitro group, cyano group, an optionally substituted C1-6 alkyl group, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C1-6 alkoxy group, an optionally substituted C2-6 alkenyloxy group, an optionally substituted C2-6 alkynyloxy group, an optionally substituted C1-6 alkylthio group, an optionally substituted C2-6 alkenylthio group, an optionally substituted C2-6 alkynylthio group, a C2-7 fatty acyl group, an optionally substituted carbamoyl group, an arylacyl group, a heteroaryl acyl group, an optionally substituted amino group, an optionally substituted C1-6 alkylsulfonyl group, an optionally substituted C2-6 alkenylsulfonyl group, an optionally substituted C2-6 alkynylsulfonyl group, an optionally substituted C1-6 alkylsulfinyl group, an optionally substituted C2-6 alkenylsulfinyl group, an optionally substituted C2-6 alkynylsulfinyl group, formyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C3-8 cycloalkenyl group, an optionally substituted 5- to 14-membered non-aromatic heterocyclic group, an optionally substituted C6-14 aromatic hydrocarbon cyclic group and an optionally substituted 5- to 14-membered aromatic heterocyclic group) or a salt thereof; (15) the compound according to the above-mentioned (14) or a salt thereof, in which R1 is cyano group; (16) the compound according to the above-mentioned (14) or a salt thereof, in which R1is carboxyl group; (17) the compound according to the above-mentioned (14) or a salt thereof, in which R1 is a carbamoyl group represented by the formula: 
in which R5 and R6 have the same meanings as defined above; (18) the compound according to the above-mentioned (14) or a salt thereof, in which R2 is a hydrogen atom; (19) the compound according to the above-mentioned (14) or a salt thereof, in which R7 and the substituent groups other than R7 in the ring A are selected from the above-mentioned substituent group a; (20) the compound according to the above-mentioned (14) or a salt thereof, in which R7 is hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group or an optionally substituted C1-6 alkoxy group; (21) the compound according to the above-mentioned (14) or a salt thereof, in which R8 is a phenyl group, pyridyl group, furyl group or a thienyl group, each of which may have a substituent group; (22) the compound according to the above-mentioned (14) or a salt thereof, in which R8 is a phenyl group, pyridyl group, furyl group or a thienyl group, each of which may be substituted with a halogen atom; (23) the compound according to the above-mentioned (1), in which the compound is any one selected from 2-amino-6-(2-furyl)-5-(4-pyridyl)-3-pyridinecarbonitrile, 2-amino-6-(3-fluorophenyl)-5-(4-pyridyl)-3-pyridinecarbonitrile, 2-amino-6-(2-furyl)-5-(4-methoxy-3-pyridyl)-3-pyridinecarbonitrile, 2-amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile, 2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinonitrile, 2-amino-6-(2-furyl)-5-(1-methyl-6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile, 2-amino-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile and 2-amino-6-(3-fluorophenyl)-5-(1-methyl-6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile, or a salt thereof; (24) a pharmaceutical composition comprising a compound represented by the formula: 
(wherein R1 represents cyano group, carboxyl group or an optionally substituted carbamoyl group; R2 represents hydrogen atom, hydroxyl group, an optionally substituted C1-6 alkoxy group, an optionally substituted C6-14 aromatic hydrocarbon cyclic group or an optionally substituted 5- to 14-membered aromatic heterocyclic group; and R3 and R4 are the same as or different from each other and each represents a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C6-14 aromatic hydrocarbon cyclic group, a 5- to 14-membered non-aromatic heterocyclic group or a 5- to 14-membered aromatic heterocyclic group which may have a substituent group, respectively, provided that the cases where (1) R1 is cyano group, R2 is 4-bromo-2-thienyl group, R3 is 3,4-dimethoxyphenyl group and R4 is 2-thienyl group, (2) R1 is cyano group, R2 is hydrogen atom and each of R3 and R4 is phenyl group, (3) R1 is cyano group, R2 is 4-chloro-phenyl group, R3 is phenyl group and R4 is 4-(3,4-dichlorophenyl)-1-oxo-2(1H)-phthalazinyl group, (4) R1 is cyano group, R2 is hydrogen atom, R3 is 4-pyridyl group and R4 is 1-piperazinyl group, (5) R1 is cyano group, R2 is hydrogen atom, R3 is 4-pyridyl group and R4 is 1-pyridyl group, (6) R1 is cyano group, R2 is hydrogen atom, R3 is 4-pyridyl group and R4 is 4-diphenylmethyl-1-piperazinyl group, (7) R1 is cyano group, R2 is hydrogen atom, R3 is 4-pyridyl group and R4 is 4-morpholinyl group, (8) R1 is cyano group, R2 is 4-methylphenyl group and each of R3 and R4 is phenyl group, and (9) R1 is cyano group and each of R2, R3 and R4 is phenyl group are excluded) or a salt thereof; (25) the composition according to the above-mentioned (24), which is an agent for treating or preventing a disease to which an adenosine receptor relates; (26) the composition according to the above-mentioned (24), which is an agent for treating or preventing a disease to which an adenosine A2 receptor relates; (27) the composition according to the above-mentioned (24), which is an agent for treating or preventing a disease to which an adenosine A2B receptor relates; (28) the composition according to the above-mentioned (24), which is an adenosine receptor antagonist; (29) the composition according to claim 24, which is an adenosine A2 receptor antagonist; (30) the composition according to the above-mentioned (24), which is an adenosine A2B receptor antagonist; (31) the composition according to the above-mentioned (24), which is used for promoting defecation; (32) the composition according to the above-mentioned (24), which is an agent for treating, preventing or improving constipation; (33) the composition according to the above-mentioned (24), in which the constipation is functional constipation; (34) the composition according to the above-mentioned (24), which is an agent for treating irritable bowel syndrome, constipation accompanying irritable bowel syndrome, organic constipation, constipation accompanying enteroparalytic ileus, constipation accompanying congenital digestive tract dysfunction or constipation accompanying ileus; (35) the composition according to the above-mentioned (24), which is used for evacuating intestinal tracts at the time of examination of digestive tracts or before and after an operation; (36) the composition according to the above-mentioned (24), which is an agent for treating or preventing diabetes, diabetic complications, diabetic retinopathy, obesity or asthma; (37) the composition according to the above-mentioned (24), which is a hypoglycemic agent, an improving agent for impaired glucose tolerance and a potentiating agent for insulin sensitivity; (38) the composition according to the above-mentioned (24), which is a hypotensive agent, a diuretic, a therapeutic agent for osteoporosis, an anti-Parkinson""s disease agent, an anti-Alzheimer""s disease agent, a therapeutic agent for inflammatory intestinal diseases or a therapeutic agent for Crohn""s disease, etc.
That is, the present invention is a pharmaceutical composition comprising the above-mentioned 2-aminopyridine compound or a pharmacologically acceptable salt thereof and a pharmaceutically acceptable carrier, use of the above-mentioned compound or a pharmacologically acceptable salt thereof for producing an agent for treating or preventing a disease to which an adenosine receptor relates, and a method of treating or preventing a disease to which an adenosine receptor relates, by administering a pharmacologically effective dose of the above-mentioned compound or a pharmacologically acceptable salt thereof to a patient.
Hereinafter, the meanings of symbols, terms etc. used in the present specification are described, and the present invention is described in detail.
The xe2x80x9cantagonistxe2x80x9d in this specification refers to an agent having affinity for adenosine receptors, particularly adenosine A2 receptor (most preferably A2B receptor) and inactivating the receptor.
In this specification, the xe2x80x9cdisease to which an adenosine receptor relatesxe2x80x9d means a disease to which an adenosine A1 receptor, A2a receptor, A2b receptor or A3 receptor relates. For example, various kinds of constipation, irritable bowel syndrome, constipation accompanying irritable bowel syndrome, organic constipation, constipation accompanying intestinal paralytic ileus, constipation accompanying congenital digestive tract dysfunction, constipation accompanying ileus, diabetes, diabetic complications, diabetic retinopathy, obesity or asthma, or a disease against which a hypoglycemic agent, an improving agent for impaired glucose tolerance, a potentiating agent for insulin sensitivity, a hypotensive agent, a diuretic, a therapeutic agent for osteoporosis, an anti-Parkinson""s disease agent, an anti-Alzheimer""s disease agent, a therapeutic agent for inflammatory intestinal diseases or a therapeutic agent for Crohn""s disease is efficacious.
The term xe2x80x9cand/orxe2x80x9d used in this specification refers to both of xe2x80x9candxe2x80x9d and xe2x80x9corxe2x80x9d.
The structural formulae of the compound in this specification may, for convenience"" sake, indicate a certain isomer, but the present invention encompasses all possible isomers which can occur in the structures of the compound, for example, geometric isomer, optical isomer based on asymmetrical carbon, rotational isomer, stereoisomer and tautomer, as well as a mixture of such isomers, so the compound of the invention may be any isomers or a mixture thereof without limitation to the formulae shown for convenience"" sake. Accordingly, the compound of the present invention can have an intramolecular asymmetrical carbon to occur as optically active isomers or racemic modifications, and any of such compounds are included in the present invention without limitation. Further, crystal polymorphism may present also without limitation, and it may be in a single crystal form or a mixed crystal form. The compound (I) according to the present invention or a salt thereof may be anhydrides or hydrates, any of which fall under the claims in the present specification. Metabolites formed by decomposition of the Compound (I) according to the present invention in vivo, as well as prodrugs of the compound (I) according to the present invention or a salt thereof also fall under the claims in the present specification.
As the xe2x80x9chalogen atomxe2x80x9d used in the present specification, for example, atoms such as fluorine atom, chlorine atom, bromine atom, iodine atom etc. may be proposed, and fluorine atom, chlorine atom and bromine atom are preferred.
The xe2x80x9cC1-6 alkyl groupxe2x80x9d used in this specification refers to an alkyl group containing 1 to 6 carbon groups, and examples thereof include linear or branched alkyl groups such as methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-ethylpropyl group, n-hexyl group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1,-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group or 3-methylpentyl group may be proposed.
The xe2x80x9cC2-6 alkenyl groupxe2x80x9d used in this specification refers to an alkenyl group containing 2 to 6 carbon atoms. As the preferable examples thereof, for example, vinyl group, allyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 2-methyl-1-propenyl group, 3-methyl-1-propenyl group, 2-methyl-2-propenyl group, 3-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 1-hexenyl group, 1,3-hexanedienyl group, 1,6-hexanedienyl group etc. may be proposed.
The xe2x80x9cC2-6 alkynyl groupxe2x80x9d used in this specification refers to an alkynyl group containing 2 to 6 carbon atoms. As the preferable examples thereof, for example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 3-methyl-1-propynyl group, 1-ethynyl-2-propynyl group, 2-methyl-3-propynyl group, 1-pentynyl group, 1-hexynyl group, 1,3-hexanediynyl group, 1,6-hexanediynyl group etc. may be proposed.
The xe2x80x9cC1-6 alkoxy groupxe2x80x9d used in this specification refers to an alkoxy group containing 1 to 6 carbon groups, for example, methoxy group, ethoxy group, n-propoxy group, iso-propoxy group, sec-propoxy group, n-butoxy group, iso-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, iso-pentyloxy group, sec-pentyloxy group, n-hexoxy group, iso-hexoxy group, 1,1-dimethylpropyloxy group, 1,2-dimethylpropoxy group, 2,2-dimethylpropyloxy group, 2-ethylpropoxy group, 1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group, 1,1,2-trimethylpropoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2,3-dimethylbutyloxy group, 1,3-dimethylbutyloxy group, 2-ethylbutoxy group, 1,3-dimethylbutoxy group, 2-methylpentoxy group, 3-methylpentoxy group, hexyloxy group etc.
The xe2x80x9cC2-6 alkenyloxy groupxe2x80x9d used in this specification refers to an alkenyloxy group containing 2 to 6 carbon atoms. As the preferable group, for example, vinyloxy group, allyloxy group, 1-propenyloxy group, 2-propenyloxy group, isopropenyloxy group, 2-methyl-1-propenyloxy group, 3-methyl-1-propenyloxy group, 2-methyl-2-propenyloxy group, 3-methyl-2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 1-pentenyloxy group, 1-hexenyloxy group, 1,3-hexanedienyloxy group, 1,6-hexanedienyloxy group etc. may be proposed.
The xe2x80x9cC2-6 alkynyloxy groupxe2x80x9d used in this specification refers to an alkynyloxy group containing 2 to 6 carbon atoms. Preferably, for example, ethynyloxy group, 1-propynyloxy group, 2-propynyloxy group, 1-butynyloxy group, 2-butynyloxy group, 3-butynyloxy group, 3-methyl-1-propynyloxy group, 1-ethynyl-2-propynyloxy group, 2-methyl-3-propynyloxy group, 1-pentynyloxy group, 1-hexynyloxy group, 1,3-hexanediynyloxy group, 1,6-hexanediynyloxy group etc. may be proposed.
The xe2x80x9cC1-6 alkylthio groupxe2x80x9d used in this specification refers to an alkoxy group containing 1 to 6 carbon groups. For example, methylthio group, ethylthio group, n-propylthio group, iso-propylthio group, sec-propylthio group, n-butylthio group, iso-butylthio group, sec-butylthio group, tert-butylthio group, n-pentylthio group, iso-pentylthio group, sec-pentylthio group, n-hexylthio group, iso-hexylthio group, 1,1-dimethylpropylthio group, 1,2-dimethylpropylthio group, 2,2-dimethylpropylthio group, 2-ethylpropylthio group, 1-methyl-2-ethylpropylthio group, 1-ethyl-2-methylpropylthio group, 1,1,2-trimethylpropylthio group, 1,1,2-trimethylpropylthio group, 1,1,-dimethylbutylthio group, 1,2-dimethylbutylthio group, 2,2-dimethylbutylthio group, 2,3-dimethylbutylthio group, 1,3-dimethylbutylthio group, 2-ethylbutylthio group, 1,3-dimethylbutylthio group, 2-methylpentylthio group, 3-methylpentylthio group etc. may be proposed. The xe2x80x9cC2-6 alkenylthio groupxe2x80x9d used in this specification refers to an alkenylthio group containing 2 to 6 carbon atoms. The preferable examples thereof include vinylthio group, allylthio group, 1-propenylthio group, 2-propenylthio group, isopropenylthio group, 2-methyl-1-propenylthio group, 3-methyl-1-propenylthio group, 2-methyl-2-propenylthio group, 3-methyl-2-propenylthio group, 1-butenylthio group, 2-butenylthio group, 3-butenylthio group, 1-pentenylthio group, 1-hexenylthio group, 1,3-hexanedienylthio group, 1,6-hexanedienylthio group, etc. The xe2x80x9cC2-6 alkynylthio groupxe2x80x9d used in this specification refers to an alkynylthio group containing 2 to 6 carbon atoms. The preferable examples thereof include ethynylthio group, 1-propynylthio group, 2-propynylthio group, 1-butynylthio group, 2-butynylthio group, 3-butynylthio group, 3-methyl-1-propynylthio group, 1-ethynyl-2-propynylthio group, 2-methyl-3-propynylthio group, 1-pentynylthio group, 1-hexynylthio group, 1,3-hexanediynylthio group, 1,6-hexanediynylthio group, etc.
The xe2x80x9cC3-8 cycloalkyl groupxe2x80x9d used in this specification refers to a cycloalkyl group containing 3 to 8 carbon atoms, and examples thereof include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group etc.
The xe2x80x9cC3-8 cycloalkenyl groupxe2x80x9d used in this specification refers to a C3-8 cycloalkenyl group containing 3 to 8 carbon atoms. For example, cyclopropen-1-yl, cyclopropen-3-yl, cyclobuten-1-yl, cyclobuten-3-yl, 1,3-cyclobutadien-1-yl, cyclopenten-1-yl, cyclopenten-3-yl, cyclopenten-4-yl, 1,3-cyclopentadien-1-yl, 1,3-cyclopentadien-2-yl, 1,3-cyclopentadien-5-yl, cyclohexen-1-yl, cyclohexen-3-yl, cyclohexen-4-yl, 1,3-cyclohexadien-1-yl, 1,3-cyclohexadien-2-yl, 1,3-cyclohexadien-5-yl, 1,4-cyclohexadien-3-yl, 1,4-cyclohexadien-1-yl, cyclohepten-1-yl, cyclohepten-3-yl, cyclohepten-4-yl, cyclohepten-5-yl, 1,3-cyclohepten-2-yl, 1,3-cyclohepten-1-yl, 1,3-cycloheptadien-5-yl, 1,3-cycloheptadien-6-yl, 1,4-cycloheptadien-3-yl, 1,4-cycloheptadien-2-yl, 1,4-cycloheptadien-1-yl,1,4-cycloheptadien-6-yl, 1,3,5-cycloheptatrien-3-yl, 1,3,5-cycloheptatrien-2-yl, 1,3,5-cycloheptatrien-1-yl, 1,3,5-cycloheptatrien-7-yl, cycloocten-1-yl, cycloocten-3-yl, cycloocten-4-yl, cycloocten-5-yl, 1,3-cyclooctadien-2-yl, 1,3-cyclooctadien-1-yl, 1,3-cyclooctadien-5-yl, 1,3-cyclooctadien-6-yl, 1,4-cyclooctadien-3-yl, 1,4-cyclooctadien-2-yl, 1,4-cyclooctadien-1-yl, 1,4-cyclooctadien-6-yl, 1,4-cyclooctadien-7-yl, 1,5-cyclooctadien-3-yl, 1,5-cyclooctadien-2-yl, 1,3,5-cyclooctatrien-3-yl, 1,3,5-cyclooctatrien-2-yl, 1,3,5-cyclooctatrien-1-yl, 1,3,5-cyclooctatrien-7-yl, 1,3,6-cyclooctatrien-2-yl, 1,3,6-cyclooctatrien-1-yl, 1,3,6-cyclooctatrien-5-yl, 1,3,6-cyclooctatrien-6-yl group, etc. may be proposed.
The xe2x80x9c5- to 14-membered non-aromatic heterocyclic groupxe2x80x9d used in this specification refers to a monocyclic, bicyclic or tricyclic, 5- to 14-membered non-aromatic heterocyclic group containing at least one heteroatom selected from nitrogen atom, sulfur atom and oxygen atom. Specific examples of the group include pyrrolidinyl group, pyrrolyl group, piperidinyl group, piperazinyl group, imidazolyl group, pyrazolidyl group, imidazolidyl group, morpholyl group, tertrahydrofuryl group, tetrahydropyranyl group, pyrrolinyl group, dihydrofuryl group, dihydropyranyl group, imidazolinyl group, oxazolinyl group, etc. Further, the non-aromatic heterocyclic group also includes a group derived from a pyridone ring or a non-aromatic fused ring (for example, a group derived from a phthalimide ring, succinimide ring, etc.).
The xe2x80x9cC6-14 aromatic hydrocarbon cyclic groupxe2x80x9d and xe2x80x9carylxe2x80x9d used in this specification refer to an aromatic hydrocarbon cyclic group containing 6 to 14 carbon atoms, and include a monocyclic group and a condensed ring such as bicyclic group, tricyclic group etc. Specific examples of this group include phenyl group, indenyl group, 1-naphthyl group, 2-naphthyl group, azulenyl group, heptalenyl group, biphenyl group, indacenyl group, acenaphthyl group, fluorenyl group, phenalenyl group, phenanthrenyl group, anthracenyl group, cyclopentacyclooctenyl group, benzocyclooctenyl group, etc. may be proposed.
In this specification, the xe2x80x9c5- to 14-membered aromatic heterocyclic groupxe2x80x9d and xe2x80x9cheteroarylxe2x80x9d refer to a monocyclic, bicyclic or tricyclic, 5- to 14-membered aromatic heterocyclic group containing at least one heteroatom selected from nitrogen atom, sulfur atom and oxygen atom. Specific examples of the group include, for example, 1) nitrogen-containing aromatic heterocyclic groups such as pyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl group, tetrazolyl group, benzotriazolyl group, pyrazolyl group, imidazolyl group, benzimidazolyl group, indolyl group, isoindolyl group, indolizinyl group, purinyl group, indazolyl group, quinolyl group, isoquinolyl group, quinolizyl group, phthalazyl group, naphthyridinyl group, quinoxalyl group, quinazolinyl group, cinnolinyl group, pteridinyl group, imidazotriazinyl group, pyrazinopyridazinyl group, acridinyl group, phenanthridinyl group, carbazolyl group, carbazolinyl group, pyrimidinyl group, phenanthrolinyl group, phenacynyl group, imidazopyridinyl group, imidazopyrimidinyl group, pyrazolopyridinyl group, pyrazolopyridinyl group, etc.; 2) sulfur-containing aromatic heterocyclic groups such as thienyl group, benzothienyl group, etc.; 3) oxygen-containing aromatic heterocyclic groups such as furyl group, pyranyl group, cyclopentapyranyl group, benzofuryl group, isobenzofuryl group, etc.; and 4) aromatic heterocyclic group containing two or more heteroatoms, such as thiazolyl group, isothiazolyl group, benzothiazolyl group, benzthiadiazolyl group, phenothiazinyl group, isoxazolyl group, furazanyl group, phenoxazinyl group, oxazolyl group, isoxazoyl group, benzoxazolyl group, oxadiazolyl group, pyrazolooxazolyl group, imidazothiazolyl group, thienofuranyl group, furopyrrolyl group, pyridoxazinyl group, etc.
The xe2x80x9cC2-7 fatty acyl groupxe2x80x9d used in this specification refers to an atomic group derived by removing an OH group from a carboxyl group of a C2-7 fatty carboxylic acid. As the preferable group thereof, for example, acetyl group, propionyl group, butyroyl group, etc. may be proposed.
The xe2x80x9carylacyl groupxe2x80x9d used in this specification refers to a carbonyl group substituted with a C6-14 aromatic hydrocarbon cyclic group, and the xe2x80x9cheteroarylacyl groupxe2x80x9d refers to a carbonyl group substituted with a 5- to 14-membered aromatic heterocyclic group. The xe2x80x9cC6-14 aromatic hydrocarbon cyclic groupxe2x80x9d and xe2x80x9c5- to 14-membered aromatic heterocyclic groupxe2x80x9d have the same meaning as defined above.
Preferable examples of the xe2x80x9cC1-6 alkylsulfonyl groupxe2x80x9d, xe2x80x9cC2-6 alkenylsulfonyl groupxe2x80x9d and xe2x80x9cC2-6 alkynylsulfonyl groupxe2x80x9d used in this specification include methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, iso-propylsulfonyl group, n-butylsulfonyl group, tert-butylsulfonyl group, vinylsulfonyl group, allylsulfonyl group, iso-propenylsulfonyl group, iso-pentenylsulfonyl group, ethynylsulfonyl group etc. Preferable examples of the xe2x80x9cC1-6 alkylsulfinyl groupxe2x80x9d, xe2x80x9cC2-6 alkenylsulfinyl groupxe2x80x9d and xe2x80x9cC2-6 alkynylsulfinyl groupxe2x80x9d used in this specification include methylsulfinyl group, ethylsulfinyl group, n-propylsulfinyl group, iso-propylsulfinyl group, n-butylsulfinyl group, tert-butylsulfinyl group, vinylsulfinyl group, allylsulfinyl group, iso-propenylsulfinyl group, iso-pentenylsulfinyl group, ethynylsulfinyl group, etc.
As the xe2x80x9csubstituent groupxe2x80x9d in the xe2x80x9coptionally substituted amino groupxe2x80x9d used in this specification, for example, one or two groups selected from a C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C1-6 alkylsulfonyl group, C2-6 alkenylsulfonyl group, C2-6 alkynylsulfonyl group, C1-6 alkylcarbonyl group, C2-6 alkenylcarbonyl group and C2-6 alkynylcarbonyl group, each of which may have a substituent group may be proposed, and the substituent groups may be bound together to form a 3- to 8-membered nitrogen-containing ring. Preferable examples of the xe2x80x9csubstituent groupxe2x80x9d of the above-mentioned C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C1-6 alkylsulfonyl group, C2-6 alkenylsulfonyl group, C2-6 alkynylsulfonyl group, C1-6 alkylcarbonyl group, C2-6 alkenylcarbonyl group and C2-6 alkynylcarbonyl group include hydroxyl group, a halogen atom, nitrile group, a C1-6 alkoxy group, a C1-6 alkylthio group, etc. Specifically, as the particularly preferable examples of the above-mentioned xe2x80x9camino group which may have a substituent groupxe2x80x9d, methylamino group, ethylamino group, n-propylamino group, iso-propylamino group, n-butylamino group, iso-butylamino group, tert-butylamino group, n-pentylamino group, iso-pentylamino group, neopentylamino group, n-hexylamino group, 1-methylpropylamino group, 1,2-dimethylpropylamino group, 2-ethylpropylamino group, 1-methyl-2-ethylpropylamino group, 1-ethyl-2-methylpropylamino group, 1,1,2-trimethylpropylamino group, 1-methylbutylamino group, 2-methylbutylamino group, 1,1-dimethylbutylamino group, 2,2-dimethylbutylamino group, 2-ethylbutylamino group, 1,3-dimethylbutylamino group, 2-methylpentylamino group, 3-methylpentylamino group, N,N-dimethylamino group, N,N-diethylamino group, N,N-di(n-propyl)amino group, N,N-di(iso-propyl)amino group, N,N-di(n-butyl)amino group, N,N-di(iso-butyl)amino group, N,N-di(tert-butyl)amino group, N,N-di(n-pentyl)amino group, N,N-di(iso-pentyl)amino group, N,N-di(n-pentyl)amino group, N,N-di(n-hexyl)amino group, N,N-di(1-methylpropyl)amino group, N,N-di(1,2-dimethylpropyl)amino group, N-methyl-N-ethylamino group, N-ethyl-N-(n-propyl)amino group, N-methyl-N-(i-propyl)amino group, vinylamino group, allylamino group, (1-propenyl)amino group, isopropenylamino group, (1-buten-1-yl)amino group, (1-buten-2-yl)amino group, (1-buten-3-yl)amino group, (2-buten-1-yl)amino group, (2-buten-2-yl)amino group, N,N-divinylamino group, N,N-diallylamino group, N,N-di(1-propenyl)amino group, N,N-isopropenylamino group, N-vinyl-N-allylamino group, ethynylamino group, 1-propynylamino group, 2-propynylamino group, butynylamino group, pentynylamino group, hexynylamino group, N,N-diethynylamino group, N,N-(1-propynyl)amino group, N,N-(2-propynyl)amino group, N,N-dibutynylamino group, N,N-dipentynylamino group, N,N-dihexynylamino group, hydroxymethylamino group, 1-hydroxyethylamino group, 2-hydroxyethylamino group, 3-hydroxy-n-propyl group, methylsulfonylamino group, ethylsulfonylamino group, n-propylsulfonylamino group, iso-propylsulfonylamino group, n-butylsulfonylamino group, tert-butylsulfonylamino group, vinylsulfonylamino group, allylsulfonylamino group, iso-propenylsulfonylamino group, iso-pentenylsulfonylamino group, ethynylsulfonylamino group, methylcarbonylamino group, ethylcarbonylamino group, n-propylcarbonylamino group, iso-propylcarbonylamino group, n-butylcarbonylamino group, tert-butylcarbonylamino group, vinylcarbonylamino group, allylcarbonylamino group, iso-propenylcarbonylamino group, iso-pentenylcarbonylamino group, ethynylcarbonylamino group, etc.
As the xe2x80x9csubstituent groupxe2x80x9d in the xe2x80x9cwhich may have a substituent groupxe2x80x9d used in this specification, a halogen atom (for example, fluorine atom, chlorine atom, bromine atom, iodine atom etc.), hydroxyl group, nitro group, cyano group, a C1-6 alkyl group (for example, methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-ethylpropyl group, n-hexyl group, 1-methyl-2-ethylpropyl group etc.), a C2-6 alkenyl group (for example, vinyl group, allyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 2-methyl-1-propenyl group, 3-methyl-1-propenyl group, 2-methyl-2-propenyl group, 3-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 1-hexenyl group, 1,3-hexanedienyl group, 1,6-hexanedienyl group, etc.), a C2-6 alkynyl group (for example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 3-methyl-1-propynyl group, 1-ethynyl-2-propynyl group, 2-methyl-3-propynyl group, 1-pentynyl group, 1-hexynyl group, 1,3-hexanediynyl group, 1,6-hexanediynyl group, etc.), a C1-6 alkoxy group (for example, methoxy group, ethoxy group, n-propoxy group, iso-propoxy group, sec-propoxy group, n-butoxy group, iso-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, iso-pentyloxy group, sec-pentyloxy group, n-hexoxy group, etc.), a C2-6 alkenyloxy group (for example, vinyloxy group, allyloxy group, 1-propenyloxy group, 2-propenyloxy group, isopropenyloxy group, etc.), a C2-6 alkynyloxy group (for example, ethynyloxy group, 1-propynyloxy group, 2-propynyloxy group, etc.), a C1-6 alkylthio group (for example, methylthio group, ethylthio group, n-propylthio group, iso-propylthio group, sec-propylthio group, n-butylthio group, iso-butylthio group, sec-butylthio group, tert-butylthio group, etc.), a C2-6 alkenylthio group (for example, vinylthio group, allylthio group, 1-propenylthio group, 2-propenylthio group, etc.), a C2-6 alkynylthio group (for example, ethynylthio group, 1-propynylthio group, 2-propynylthio group, etc.), a C2-7 fatty acyl group (for example, acetyl group, propionyl group, butyroyl group, etc.), carbamoyl group, arylacyl group, heteroarylacyl group, amino group, a C1-6 alkylsulfonyl group, a C2-6 alkenylsulfonyl group, a C2-6 alkynylsulfonyl group, a C1-6 alkylsulfinyl group, C2-6 alkenylsulfinyl group, a C2-6 alkynylsulfinyl group (for example, methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, iso-propylsulfonyl group, n-butylsulfonyl group, tert-butylsulfonyl group, vinylsulfonyl group, allylsulfonyl group, iso-propenylsulfonyl group, iso-pentenylsulfonyl group, ethynylsulfonyl group, methylsulfinyl group, ethylsulfinyl group, n-propylsulfinyl group, iso-propylsulfinyl group, n-butylsulfinyl group, tert-butylsulfinyl group, vinylsulfinyl group, allylsulfinyl group, iso-propenylsulfinyl group, iso-pentenylsulfinyl group, ethynylsulfinyl group, etc.), formyl group, a C3-8 cycloalkyl group (for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group etc.), a C3-8 cycloalkenyl group (for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl group, etc.), a 5- to 14-membered non-aromatic heterocyclic group (for example, pyrrolidinyl group, pyrrolyl group, piperidinyl group, piperazinyl group, imidazolyl group, pyrazolidyl group, imidazolidyl group, morpholyl group, tertrahydrofuryl group, tetrahydropyranyl group, pyrrolinyl group, dihydrofuryl group, dihydropyranyl group, imidazolinyl group, oxazolinyl group, a group derived from a pyridone ring, a group derived from a phthalimide ring or succinimide ring, etc.), a C6-14 aromatic hydrocarbon cyclic group (for example, phenyl group, indenyl group, 1-naphthyl group, 2-naphthyl group, biphenyl group, indacenyl group etc.), a 5- to 14-membered aromatic heterocyclic ring (for example, pyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl group, tetrazolyl group, benzotriazolyl group, pyrazolyl group, imidazolyl group, benzimidazolyl group, indolyl group, iso-indolyl group, indolizinyl group, purinyl group, indazolyl group, quinolyl group, iso-quinolyl group, quinolizyl group, phthalazyl group, naphthylidinyl group, quinoxalyl group, quinazolinyl group, cynnolinyl group, pteridinyl group, imidazotriazinyl group, pyrazinopyridazinyl group, acridinyl group, phenanthridinyl group, carbazolyl group, carbazolinyl group, perimidinyl group, phenanthrolinyl group, phenacinyl group, imidazopyridinyl group, imidazopyrimidinyl group, pyrazolopyridinyl group, pyrazolopyridinyl group, thienyl group, benzothienyl group, furyl group, pyranyl group, cyclopentapyranyl group, benzofuryl group, iso-benzofuryl group, thiazolyl group, iso-thiazolyl group, benzothiazolyl group, benzthiadiazolyl group, phenothiazinyl group, isoxazolyl group, furazanyl group, phenoxazinyl group, oxazolyl group, isoxazoyl group, benzoxazolyl group, oxadiazolyl group, pyrazoloxazolyl group, imidazothiazolyl group, thienofuranyl group, furopyrrolyl group, pyridoxadinyl group etc.), and these substituent groups may further have substituent groups.
In the formula (I) above, R1 represents cyano group, carboxyl group or a carbamoyl group which may have a substituent group, and the most preferable group is not particularly limited. As the preferable example of the xe2x80x9csubstituent groupxe2x80x9d in the xe2x80x9ccarbamoyl group which may have a substituent groupxe2x80x9d, a group selected from a C1-6 alkyl group which may have a substituent group, a C2-6 alkenyl group which may have a substituent group, a C2-6 alkynyl group which may have a substituent group, a C3-8 cycloalkyl group which may have a substituent group, a C3-8 cycloalkenyl group which may have a substituent group, a C6-14 aromatic hydrocarbon cyclic group which may have a substituent group, a 5- to 14-membered aromatic heterocyclic group which may have a substituent group etc. may be proposed. The nitrogen atom in the carbamoyl group may be substituted with one or two groups selected from the substituent groups described above. Further, the above-mentioned substituent groups may be bound together to form a 3- to 14-membered nitrogen-containing ring (for example, pyrrolidyl group, pyrrolinyl group, piperidyl group, piperazinyl group, imidazolyl group, pyrazolidyl group, imidazolidyl group, morpholinyl group, tetrahydropyranyl group, aziridinyl group, oxiranyl group, oxathiolanyl group, phthalimidoyl group, succinimidyl group, pyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, pyrazolyl group, etc.), and the nitrogen-containing rings may further have substituent groups.
Preferable groups of R2 in the formula (I) above are not particularly limited, but more preferable groups include hydrogen atom, a C1-6 alkoxy group, phenyl, naphthyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, thienyl, furyl and imidazolyl groups, each of which may have a substituent group, and further preferably hydrogen atom.
In the formula (I) above, R3 and R4 are independent of each other and each represents a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C6-14 aromatic hydrocarbon cyclic group, a 5- to 14-membered non-aromatic heterocyclic group or a 5- to 14-membered aromatic heterocyclic group, each of which may have a substituent group, and preferable groups include a C6-14 aromatic hydrocarbon cyclic group (for example, phenyl group, naphthyl group etc.), a 5- to 14-membered non-aromatic heterocyclic group (for example, pyrrolidinyl group, pyrrolinyl group, piperidinyl group, piperazinyl group, imidazolinyl group, pyrazolidinyl group, imidazolidinyl, morpholinyl group, tetrahydropyranyl group, aziridinyl group, oxiranyl group, oxathiolanyl group, a 6-oxo-1,6-dihydropyridyl group whose nitrogen atom may be substituted etc.) or a 5- to 14-membered aromatic heterocyclic group (for example, pyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, pyrazolyl group, imidazolyl group, indolyl group, isoindolyl group, indolizinyl group, quinolinyl group, isoquinolinyl group, quinolizinyl group, phthalazinyl group, naphthyridyl group, quinoxalyl group, quinazolyl group, imidazotriazinyl group, pyrazinopyridazinyl group, thienyl group, benzothienyl group, furyl group, pyranyl group, cyclopentapyranyl group, benzofuryl group, isobenzofuryl group, thiazolyl group, isothiazolyl group, benzthiazolyl group, benzthiadiazolyl group, phenothiazyl group, isoxazolyl group, pyrazoloxazolyl group, imidazothiazolyl group, thienofuryl group, furopyrrolyl group, pyridoxazinyl group etc.), and these substituent groups may have substituent groups. As the more preferable examples of R3 and R4, for example, groups represented by the formulae: 
which may be substituted, respectively. When the above-mentioned 6-oxo-1,6-dihydropyridyl group has a substituent group, the case where the substituent group is bound to the nitrogen atom is also included.
As the xe2x80x9csubstituentxe2x80x9d in the xe2x80x9cC3-8 cycloalkyl group which may have a substituent groupxe2x80x9d, xe2x80x9cC3-8 cycloalkenyl group which may have a substituent groupxe2x80x9d, xe2x80x9cC6-14 aromatic hydrocarbon cyclic group which may have a substituent groupxe2x80x9d, xe2x80x9c5- to 14-membered non-aromatic heterocyclic group which may have a substituent groupxe2x80x9d and xe2x80x9c5- to 14-membered aromatic heterocyclic group which may have a substituent groupxe2x80x9d represented by R3 and R4, (1) one or more groups selected from hydroxyl group, a halogen atom, cyano group, nitro group, a C1-6 alkyl group which may have a substituent group, a C2-6 alkenyl group which may have a substituent group, a C2-6 alkynyl group which may have a substituent group, a C1-6 alkoxy group which may have a substituent group, a C2-6 alkenyloxy group which may have a substituent group, a C1-6 alkylthio group which may have a substituent group, a C2-6 alkenylthio group which may have a substituent group, a C2-6 alkynylthio group which may have a substituent group, a substituted carbonyl group, an amino group which may have a substituent group, a C1-6 alkylsulfonyl group which may have a substituent group, a C2-6 alkenylsulfonyl group which may have a substituent group, a C2-6 alkynylsulfonyl group which may have a substituent group, a C1-6 alkylsulfinyl group which may have a substituent group, a C2-6 alkenylsulfinyl group which may have a substituent group, a C2-6 alkynylsulfinyl group which may have a substituent group, a formyl group, a C3-8 cycloalkyl group which may have a substituent group, a C3-8 cycloalkenyl group which may have a substituent group, a 5- to 14-membered non-aromatic heterocyclic group which may have a substituent group, a C6-14 aromatic hydrocarbon cyclic group which may have a substituent group and a 5- to 14-membered aromatic heterocyclic group which may have a substituent group are preferred; (2) one or more groups selected from 1) hydroxyl group, 2) a halogen atom, 3) cyano group, 4) nitro group, 5) a C1-6 alkyl group, C2-6 alkenyl group or C2-6 alkynyl group, each of which may be substituted with at least one group selected from (i) hydroxyl group, (ii) cyano group, (iii) halogen atom, (iv) C1-6 alkylamino group, (v) di(C1-6 alkyl)amino group, (vi) C2-6 alkenylamino group, (vii) di(C2-6 alkenyl)amino group, (viii) C2-6 alkynylamino group, (ix) di(C2-6 alkynyl)amino group, (x) Nxe2x80x94C1-6 alkyl-Nxe2x80x94C2-6 alkenylamino group, (xi) Nxe2x80x94C1-6 alkyl-Nxe2x80x94C2-6 alkynylamino group, (xii) Nxe2x80x94C2-6 alkenyl-Nxe2x80x94C2-6 alkynylamino group, (xiii) aralkyloxy group, (xiv) TBDMS oxy group, (xv) C1-6 alkylsulfonylamino group, (xvi) C1-6 alkylcarbonyloxy group, (xvii) C2-6 alkenylcarbonyloxy group, (xviii) C2-6 alkynylcarbonyloxy group, (xix) Nxe2x80x94C1-6 alkylcarbamoyl group, (xx) Nxe2x80x94C2-6 alkenylcarbamoyl group and (xxi) Nxe2x80x94C1-6 alkynylcarbamoyl group, 6) a C1-6 alkoxy group, C2-6 alkenyloxy group or C2-6 alkynyloxy group, each of which may be substituted with at least one group selected from (i) C1-6 alkylamino group, (ii) aralkyloxy group and (iii) hydroxyl group, 7) a C1-6 alkylthio group, C2-6 alkenylthio group or C2-6 alkynylthio group, each of which may be substituted with at least one group selected from (i) hydroxyl group, (ii) nitrile group, (iii) halogen atom, (iv) C1-6 alkylamino group, (v) aralkyloxy group, (vi) TBDMS oxy group, (vii) C1-6 alkylsulfonylamino group, (viii) C1-6 alkylcarbonyloxy group and (ix) C1-6 alkylcarbamoyl group, 8) a carbonyl group substituted with a group selected from (i) C1-6 alkoxy group, (ii) amino group, (iii) C1-6 alkylamino group, (iv) di(C1-6 alkyl) amino group, (v) C2-6 alkenylamino group, (vi) di(C2-6 alkenyl) amino group, (vii) C2-6 alkynylamino group, (vii) di (C2-6 alkynyl) amino group, (viii) Nxe2x80x94C1-6 alkyl-Nxe2x80x94C2-6 alkenylamino group, (ix) Nxe2x80x94C1-6 alkyl-Nxe2x80x94C2-6 alkynylamino group and (x) Nxe2x80x94C2-6 alkenyl-Nxe2x80x94C2-6 alkynylamino group, 9) an amino group which may be substituted with one or two groups selected from (i) C1-6 alkyl group, (ii) C2-6 alkenyl group, (iii) C2-6 alkynyl group, (iv) C1-6 alkylsulfonyl group, (v) C2-6 alkenylsulfonyl group, (vi) C2-6 alkynylsulfonyl group, (vii) C1-6 alkylcarbonyl group, (viii) C2-6 alkenylcarbonyl group and (ix) C2-6 alkynylcarbonyl group, 10) a C1-6 alkylsulfonyl group, 11) a C2-6 alkenylsulfonyl group, 12) a C2-6 alkynylsulfonyl group, 13) a C1-6 alkylsulfinyl group, 14) a C2-6 alkenylsulfinyl group, 15) a C2-6 alkynylsulfinyl group, 16) formyl group, 17) a C3-8 cycloalkyl group or C3-8 cycloalkenyl group, each of which may be substituted with at least one group selected from (i) hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) C1-6 alkyl group, (v) C1-6 alkoxy group, (vi) C1-6 alkoxy-C1-6 alkyl group and (vii) aralkyl group, 18) a 5- to 14-membered non-aromatic heterocyclic group which may be substituted with at least one group selected from (i) hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) C1-6 alkyl group, (v) C1-6 alkoxy group, (vi) C1-6 alkoxy-C1-6 alkyl group and (vii) aralkyl group, 19) a C6-14 aromatic hydrocarbon cyclic group which may be substituted with at least one group selected from (i) hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) C1-6 alkyl group, (v) C1-6 alkoxy group, (vi) C1-6 alkoxy-C1-6 alkyl group and (vii) aralkyl group, and 20) a 5- to 14-membered aromatic heterocyclic group which may be substituted with at least one group selected from (i) hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) C1-6 alkyl group, (v) C1-6 alkoxy group, (vi) C1-6 alkoxy-C1-6 alkyl group and (vii) aralkyl group are more preferred; and (3) one or more groups selected from hydroxy group, a halogen atom (for example, fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), cyano group, nitro group, a C1-6 alkyl group (for example, methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, tert-butyl group, n-pentyl group, i-pentyl group, neopentyl group, n-hexyl group, etc.), a C2-6 alkenyl group (for example, vinyl group, allyl group, 1-propenyl group, isopropenyl group, etc.), a C2-6 alkynyl group (for example, ethynyl group, 1-propynyl group, 2-propynyl group, butynyl group, pentynyl group, hexynyl group, etc.), a C1-6 alkoxy group (methoxy group, ethoxy group, n-propoxy group, iso-propoxy group, n-butoxy group, etc.) and a C2-6 alkenyloxy group (vinyloxy group, allyloxy group, 1-propenyloxy group, isopropenyloxy group, etc.) are the most preferred.
The preferable mode of the compound represented by the formula (I) above according to the present invention or a salt thereof is not particularly limited, among which more preferable mode is a compound or a salt thereof, wherein R3 is a group represented by the formula: 
(wherein R7 represents a group selected from the above substituent group b; and ring A represents a nitrogen-containing 6-membered ring which may be substituted with 1 to 4 groups selected from the above substituent group b), and still more preferable mode is a compound represented by the formula: 
(wherein R1 represents cyano group, carboxyl group or an optionally substituted carbamoyl group; R2 represents hydrogen atom, hydroxyl group, a C1-6 alkoxy group which may have a substituent group, a C1-6 alkylthio group which may have a substituent group, a C6-14 aromatic hydrocarbon cyclic group which may have a substituent group or a 5- to 14-membered aromatic heterocyclic group which may have a substituent group; R7 represents a group selected from the above substituent group b; R8 represents a C6-14 aromatic hydrocarbon cyclic group or a 5- to 14-membered aromatic heterocyclic group, each of which may have a substituent group; ring A represents a nitrogen-containing 6-membered ring which may be substituted with 1 to 4 groups selected from the substituent group b above) or a salt thereof. The preferable mode of each R1, R7 and R8 are as described above.
In this specification, the xe2x80x9csaltxe2x80x9d is not particularly limited insofar as it forms a salt with the compound accroding to the present invenvention and is pharmacologically acceptable. Preferably, hydrogen halides (for example, hydrofluoride, hydrochloride, hydrobromide and hydroiodide), inorganic acid salts (for example, sulfate, nitrate, perchlorate, phosphate, carbonate and bicarbonate), organic carboxylic acid salts (for example, acetate, trifluoroacetate, oxalate, maleate, tartrate, fumarate and citrate), organic sulfonic acid salts (for example, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate and camphor sulfonate), amino acid salts (for example, aspartate and glutamate), quaternary amine salts, alkali metal salts (for example, sodium salt and potassium salt), alkaline earth metal salts (for example, magnesium salt and calcium salt), etc. may be proposed., and hydrochloride, oxalte etc. are more preferred as the xe2x80x9cpharmacologically acceptable saltxe2x80x9d.
Production Process
A typical process for producing the compound according to the present invention represented by the above formula (I) will be shown below. Here, the xe2x80x9croom temperaturexe2x80x9d mentioned below refers to 0 to around 40xc2x0 C.
Production Process 1
In the formula, R3axe2x80x2 represents a 5- to 14-membered aromatic heterocyclic group which has a nitrogen atom at the 4-position and may have a substituent group (for example, 4-pyridyl group, 4-pyrimidinyl group, 4-pyridazinyl group, etc.); R4a represents a C6-14 aromatic hydrocarbon cyclic group which may have a substituent group or a 5- to 14-membered aromatic heterocyclic group which may have a substituent group; and R9 represents a C1-8 alkyl group. The 1,2-biaryl-1-ethanone compound (ii)xe2x80x2 as the starting material of the compound represented by the above formula (I) according to the present invention can be produced by reacting the aromatic carboxylate (i) with a 4-methyl aromatic heterocyclic compound represented by the formula R3axe2x80x2xe2x80x94CH3 in the presence of a base in a solvent, followed by dealcoholic condensation. The base used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, secondary amine metal salts represented by lithium bis(trimethylsilyl)amide and lithium diisopropylamide may be proposed. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol may be proposed. The reaction temperature is usually xe2x88x9278xc2x0 C. to room temperature, preferably around 0xc2x0 C.
Production Process 2
In the formula, R3axe2x80x3 represents a C6-14 aromatic hydrocarbon cyclic group which may have a substituent group or a 5- to 14-membered aromatic heterocyclic group which may have a substituent group; R4a has the same meaning as defined above; and X1 represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group. The 1,2-biaryl-1-ethanone compound (ii)xe2x80x3 as the starting material for producing the compound represented by the above formula (I) according to the present invention can also be produced by Production Process 2 instead of the above-mentioned Production Process 1. That is, it is produced by allowing an aromatic trialkylsilyl cyanohydrin compound prepared from the aromatic aldehyde (iii) to be condensed with a compound represented by the formula R3axe2x80x3xe2x80x94CH2X1 in the presence of a base; and then allowing a fluorine compound to act, followed by decyanating trialkylsilylation. As the reagent used for preparing the aromatic trialkylsilyl cyanohydrin from (iii), using a trialkylsilyl cyanide compound represented by trimethylsilyl cyanide is preferred. In this case, simultaneously using a metal salt such as zinc (II) iodide as a catalyst is also preferred, and it makes possible to achieve rapid reaction. The base used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, secondary amine metal salts represented by lithium bis(trimethylsilyl)amide and lithium diisopropylamide, etc. may be proposed. The fluorine compound used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, hydrofluoric acid, hydrofluoride amine, and more preferably tetrabutylammonium fluoride may be proposed. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol may be proposed. The reaction temperature is preferably xe2x88x9278xc2x0 C. to room temperature.
Production Process 3
In the formula, R3a and R4a represent a C6-14 aromatic hydrocarbon cyclic group which may have a substituent group or a 5- to 14-membered aromatic heterocyclic group which may have a substituent group. The 3-(dimethylamino)-2-propen-1-one derivative (iv) is the starting material for producing the compound (I) according to the present invention. (iv) can be produced by allowing N,N-dimethylformamide dimethylacetal to act on active methylene of (ii) produced in the above-mentioned Production Process 1 or 2. This reaction is carried out most preferably in the absence of a solvent, but preferable results can be achieved even if it is carried out by diluting with a solvent which is inert to the reaction and dissolves the starting material to a certain degree (for example, N,N-dimethylformamide, tetrahydrofuran, dioxane, N,N-methylpyrrolidone, benzene, toluene etc.), etc. The reaction temperature is usually room temperature to 120xc2x0 C., more preferably around 100xc2x0 C.
Using the compounds obtained in the above-mentioned Production Processes 1 to 3, the compound (vii) according to the present invention can be produced as follows.
Production Process 4
In the formula, R3a and R4a have the same meanings as defined above; and X2 represents a halogen atom. The compound (vii) can be produced via the intermediates (v) and (vi) in this order from the compound (iv) obtained in the above-mentioned Production Process 3 (steps 4-(1) to 4-(3) in the formula). The 2-oxo-1,2-dihydro-3-pyridylcarbonitrile derivative (v) can be produced by reacting (iv) with 2-cyanoacetamide in the presence of a base (step 4-(1)). The base used varies depending on the starting material, the solvent used etc., and is not particularly limited insofar as it is inert to the reaction. Preferably, an alkali metal alkoxide such as sodium methoxide, sodium ethoxide or potassium tert-butoxide may be proposed. Further, also by using alkali metal carbonates such as potassium carbonate or sodium carbonate, a preferable result can be obtained. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol etc. may be proposed. The reaction temperature is usually room temperature to 120xc2x0 C., more preferably around 80xc2x0 C. The 2-halogeno-3-pyridylcarbonitrile derivative (vi) can be produced by converting an oxo group in (v) into a halogen atom (step 4-(2)). The reaction is conducted preferably in the absence of a solvent. Further, when it is conducted by being suspending in a solvent which is inert to the reaction and dissolves the starting material to a certain degree (for example, acetonitrile, dioxane, tetrahydrofuran etc.), a preferable result can be also obtained. The halogenating agent used for converting the oxo group into a halogen atom varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, phosphorus oxychloride, phosphorus oxybromide etc. may be proposed. It is preferably conducted by acting these halogenating agent at a reaction temperature of 70 to 120xc2x0 C. Further, when a tertiary amine such as tripropylamine, a quaternary amine salt such as tetraethyl ammonium chloride, or N,N-dimethylformamide etc., is added to this reaction system, the reaction is further promoted and a good result can be obtained. The 2-amino-3-pyridylcarbonitrile compound (vii) according to the present invention can be produced by reacting X2 (halogen atom) in (vi) with ammonia (step 4-(3)). The present reaction is carried out usually at 0 to 150xc2x0 C., more preferably in an autoclave (50 to 100xc2x0 C.). The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, N,N-dimethylformamide, 1-methyl pyrrolidinone etc. may be proposed.
Production Process 5
In the formula, R3b represents a C6-14 aromatic hydrocarbon cyclic group which may have a substituent group or a 5- to 14-membered aromatic heterocyclic group which may have a substituent group; X3 represents a halogen atom; and Y represents a C1-6 alkyl group. The aryl tin reagent (ix) used in the xe2x80x9cstep 6-(4)xe2x80x9d in Production Process 6 can be produced by lithiation of an aryl halide (viii); and then allowing halogenotrialkyl tin to act. In the lithiation reaction, use of alkyl lithium such as n-butyl lithium, sec-butyl lithium, tert-butyl lithium etc. is preferred. The halogenotrialkyl tin used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, trimethyltin chloride such as chlorotributyltin, or triethyltin bromide etc. may be proposed. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, an ether such as tetrahydrofuran, diethyl ether etc. may be proposed. The reaction temperature is preferably xe2x88x92100xc2x0 C. to room temperature.
When the 3-(dimethylamino)-2-propen-1-one derivative obtained by subjecting the compound (acetylated aryl or acetylated heteroaryl represented by the formula R4axe2x80x94COCH3) wherein R3a in (ii) was replaced by a hydrogen atom to the reaction in Production Process 3, is further subjected to xe2x80x9cstep 4-(1)xe2x80x9d in Production Process 4, the compound (x) wherein R3a in (v) was replaced by a hydrogen atom is obtained. The method of producing the compound (xiv) according to the present invention from the compound (x) is shown below.
Production Process 6
In the formula, R3b and R4a have the same meanings as defined above; and X4 represents a halogen atom. The compound (xiv) according to the present invention can be produced from (x) through steps 6-(1) to 6-(4) (intermediates (xi) to (xiii)). The compound (xi) can be produced by alkylating an oxygen atom at the 2-position in (x) with 2-halogenoacetamide in the presence of a base (step 6-(1)). The 2-halogenoacetamide used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. The reaction conducted by using 2-chloroacetamide is preferred, and conducted by further adding sodium iodide is more preferred. The base used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate and potassium carbonate may be proposed. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, ketones such as acetone or methyl ethyl ketone, alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, N,N-dimethylformamide, dimethyl sulfoxide, 1-methyl pyrrolidinone etc. may be proposed. The reaction temperature is usually 0 to 100xc2x0 C. The compound (xii) can be produced by transaminating the 2-aminocarbonylmethyloxy-3-cyanopyridine derivative (xi) in the presence of a base in a solvent (step 6-(2)). The base used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate etc. may be proposed. The solvent used varies depending on the starting material, reagents etc. and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, ketones such as acetone or methyl ethyl ketone, alcohols such as methanol, ethanol, propanol or butanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, N,N-dimethylformamide, dimethyl sulfoxide, 1-methyl pyrrolidinone etc. may be proposed. The reaction temperature is usually room temperature to 150xc2x0 C. The compound (xiii) can be produced by halogenating the 5-position of the pyridine ring in the 2-aminonicotinonitrile derivative (xii) with a halogenating agent in a solvent (step 6-(3)). As the halogenating agent used, N-bromosuccinimide, bromine etc. are preferred. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, N,N-dimethylformamide, 1-methyl pyrrolidinone etc. may be proposed. The reaction temperature is usually xe2x88x9220xc2x0 C. to room temperature. The compound (xiv) according to the present invention can be produced by allowing the aryl tin reagent obtained in Production Process 5 to act on the 2-amino-5-halogenonicotinonitrile derivative (xiii) in the presence of a palladium catalyst in a solvent to introduce an aromatic group into the 5-position of the pyridine ring in (xiii) (step 6-(4)). The palladium catalyst used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, dichlorobis(triphenylphoshine) palladium (II), palladium (II) acetate, tetrakis(triphenylphosphine) palladium (0), tris(dibenzylidene acetone) dipalladium (0) etc. may be proposed. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, toluene, xylene, N,N-dimethylformamide, 1-methyl pyrrolidinone etc. may be proposed. The reaction temperature is usually room temperature to 150xc2x0 C.
Out of the compounds represented by the above formula (I) according to the present invention, those compounds wherein R2, R3 and/or R4 represent an xcex1-hydroxy nitrogen-containing aromatic heterocyclic group having a hydroxyl group at the xcex1-position of the nitrogen atom can be produced as follows.
For example, the compound (xvi) having an xcex1-hydroxy nitrogen-containing aromatic heterocyclic group at the 5-position of the pyridine ring can be produced by hydrolysis of the xcex1-alkoxy nitrogen-containing aromatic heterocyclic compound (xv).
Production Process 7
In the formula, R4a has the same meaning as defined above; R10 represents a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group etc.; the ring A1 represents a pyridinyl group, pyrimidyl group and pyrazinyl group; and the ring A2 represents a dihydrooxopyridinyl group, a dihydrooxopyrimidyl group, a dihydropyrazinyl group or a tetrahydropyrazinyl group. The reaction is carried out preferably in an aqueous solution of a mineral acid such as, for example, hydrochloric acid, hydrobromic acid or sulfuric acid, or in a mixed solvent of the above-mentioned aqueous solution of the mineral acid and acetic acid. The reaction temperature is usually room temperature to 100xc2x0 C.
Further, a substituent can be introduced into the xcex1-hydroxy nitrogen-containing aromatic heterocyclic ring in the compound (xvi) according to the present invention obtained by the above-mentioned Production Process 7, by the following method.
Production Process 8
In the formula, R4a and ring A2 have the same meanings as defined above; R11 represents a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group etc.; and X5 represents a halogen atom. According to this process, (xvi) is reacted with an alkyl halide compound etc. in the presence of a base in a solvent, whereby the compound (xvii) having a substituent group introduced into the nitrogen atom on the ring A2 can be produced. The base used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate and potassium carbonate may be proposed. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, N,N-dimethylformamide, dimethyl sulfoxide, 1-methyl pyrrolidinone, etc. may be proposed. The reaction temperature is usually 0 to 100xc2x0 C.
Production Process 9
In the formula, R3a, R4a and X4 have the same meanings as defined above; and R2a represents a C6-14 aromatic hydrocarbon cyclic group which may have a substituent group or a 5- to 14-membered aromatic heterocyclic group which may have a substituent group. The compound (xxv) according to the present invention can be produced from (xviii) and (xix) through steps 9-(1) to 9-(6) (intermediates (xx) to (xxiv)). The compound (xx) can be produced by dehydrating condensation of (xviii) and (xix) in the presence of a base (step 9-(1)). The base used in the reaction varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, inorganic salts such as potassium hydroxide or sodium hydroxide may be proposed. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, a mixed solvent of an alcohol such as ethanol and water may be proposed. The 2-oxo-1,2-dihydro-3-pyridylcarbonitrile derivative (xxi) can be produced by reacting (xx) with 2-cyanoacetamide in the presence of a base (step 9-(2)). The reaction can be promoted in an oxygen atmosphere. The base used varies depending on the starting material, the solvent used etc., and is not particularly limited insofar as the reaction is not inhibited. Preferably, an alkali metal alkoxide such as sodium methoxide, sodium ethoxide or potassium tert-butoxide may be proposed. Otherwise, using alkali metal carbonates such as potassium carbonate or sodium carbonate can also bring about a preferable result. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol etc. may be proposed. The reaction temperature is preferably room temperature to 120xc2x0 C., more preferably around room temperature. The compound (xxii) can be produced by alkylating an oxygen atom at the 2-position in (xxi) with 2-halogenoacetamide in the presence of a base (step 9-(3)). The 2-halogenoacetamide used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. The reaction conducted by using 2-chloroacetamide is preferred, and conducted by further adding sodium iodide is more preferred. The base used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate and potassium carbonate may be proposed. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, ketones such as acetone or methyl ethyl ketone, alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, N,N-dimethylformamide, dimethyl sulfoxide, 1-methyl pyrrolidinone etc. may be proposed. The reaction temperature is usually 0 to 100xc2x0 C. The compound (xxiii) can be produced by transaminating the 2-aminocarbonylmethyloxy-3-cyanopyridine derivative (xxii) in the presence of a base in a solvent (step 9-(4)). The base used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, for example, sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate etc. may be proposed. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, N,N-dimethylformamide, dimethyl sulfoxide, 1-methylpyrrolidinone etc. may be proposed, other than ketones such as acetone or methyl ethyl ketone, alcohols such as methanol, ethanol, propanol or butanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether maybe proposed. The reaction temperature is usually room temperature to 150xc2x0 C. The compound (xxiv) can be produced by halogenating the 5-position of the pyridine ring in the 2-aminonicotinonitrile derivative (xxiii) with a halogenating agent in a solvent (step 9-(5)). The halogenating agent used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, N-bromosuccinimide, bromine etc. may be proposed. Further, the solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it it inert to the reaction and dissolves the starting material to a certain degree. Preferably, alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, N,N-dimethylformamide, 1-methyl pyrrolidinone etc. may be proposed. The reaction temperature is usually xe2x88x9220xc2x0 C. to room temperature. The compound (xxv) according to the present invention can be produced by reacting the 2-amino-5-halogenonicotinonitrile derivative (xxiv) with the aryl tin reagent obtained in Production Process 5 in the presence of a palladium catalyst in a solvent, to introduce an aromatic group into the 5-position of the pyridine ring in (xxiv) (step 9-(6)). The palladium catalyst used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, dichlorobis (triphenylphoshine) palladium (II), palladium (II) acetate, tetrakis(triphenylphosphine) palladium (0), tris(dibenzylidene acetone) dipalladium (0), dichlorobis (acetonitrile) palladium (II) etc. may be proposed. Further, the solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reacton and dissolves the starting material to a certain degree. Preferably, alcohols such as methanol, ethanol, propanol or butanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, toluene, xylene, N,N-dimethylformamide, 1-methyl pyrrolidinone etc. may be proposed The reaction temperature is usually room temperature to 150xc2x0 C.
Production Process 10
In the formula, R3a, R4a and X4 have the same meanings as defined above; R2b represents an optionally substituted alkyl group; and Y represents a lower alkyl group. The compound (xxxiii) according to the present invention can be produced from (xxvi) and (xix) through steps 10-(1) to 10-(7) (intermediates (xxvii) to (xxxii)). The compound (xxvii) can be produced by condensation of (xxvi) with (xix) (step 10-(1)). The base used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, potassium tert-butoxide etc. may be proposed. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. tert-Butanol is preferred. The reaction temperature is preferably room temperature to 120xc2x0 C., more preferably around room temperature. The compound (xxxviii) can be produced by alkylating (xxvii) with methyl halide in the presence of a base (step 10-(2)). The base used in the reaction varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, an inorganic base such as potassium carbonate etc. may be proposed. Preferable example of the methyl halide is methyl iodide. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, a ketone such as acetone or methyl ethyl ketone may be proposed. The reaction temperature is preferably room temperature to 12xc2x0 C, more preferably around room temperature. The 2-oxo-1,2-dihydro-3-pyridyl carbonitrile derivative (xxix) can be produced by reacting (xxviii) with 2-cyanoacetamide in the presence of a base (step 10-(3)). The base used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, sodium isopropoxide, potassium tert-butoxide etc. may be proposed. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, isopropanol etc. The reaction temperature is preferably 0xc2x0 C. to 120xc2x0 C. The compound (xxx) can be produced by alkylating an oxygen atom at the 2-position of (xxix) with 2-halogenoacetamide in the presence of a base (step 10-(4)) As the 2-halogenoacetamide used, 2-chloroacetamide is preferred, and the reaction in which sodium iodide is further added is more preferred. The base used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate and potassium carbonate may be proposed. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited so long as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, ketones such as acetone or methyl ethyl ketone, alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, N,N-dimethylformamide, dimethyl sulfoxide, 1-methyl pyrrolidinone, etc. may be proposed. The reaction temperature is usually 0 to 100xc2x0 C. The compound (xxxi) can be produced by transaminating the 2-aminocarbonylmethyloxy-3-cyanopyridine derivative (xxx) in the presence of a base in a solvent (step 10-(5)). The base used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate etc. may be proposed. The solvent used varies depending on the starting material, the solvent used etc., and is not particularly limited unless it is inert to the reaction. Preferably, ketones such as acetone or methyl ethyl ketone, alcohols such as methanol, ethanol, propanol or butanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, N,N-dimethylformamide, dimethyl sulfoxide, 1-methyl pyrrolidinone, etc. may be proposed. The reaction temperature is usually room temperature to 150xc2x0 C. The compound (xxii) can be produced by halogenating the 5-position of the pyridine ring in the 2-aminonicotinonitrile derivative (xxxi) with a halogenating agent in a solvent (step 10-(6)). The halogenating agent used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, N-bromosuccinimide, bromine etc. may be proposed. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, alcohols such as methanol or ethanol etc., ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether etc., N,N-dimethylformamide, 1-methyl pyrrolidinone etc. may be proposed. The reaction temperature is usually xe2x88x9220xc2x0 C. to room temperature. The compound (xxxiii) according to the present invention can be produced by allowing the aryl tin reagent obtained in Production Process 5 to act on the 2-amino-5-halogenonicotinonitrile derivative (xxxii) in the presence of a palladium catalyst in a solvent, to introduce an aromatic group into the 5-position of the pyridine ring in (xxxii) (step 10-(7)). As the palladium catalyst used is, for example, dichlorobis(triphenylphoshine) palladium (II), palladium (II) acetate, tetrakis(triphenylphosphine) palladium (0), tris(dibenzylidene acetone) dipalladium (0), dichlorobis(acetonitrile) palladium (II) etc. are preferred. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, toluene, xylene, N,N-dimethylformamide, 1-methyl pyrrolidinone etc. may be proposed. The reaction temperature is usually room temperature to 150xc2x0 C.
Production Process 11
In the formula, R2a and R4a have the same meanings as defined above; R10 represents a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group etc.; the ring A1 represents a pyridinyl group, a pyrimidyl group or a pyrazinyl group; and the ring A2 represents a dihydrooxopyridinyl group, a dihydrooxopyrimidyl group, a dihydropyrazinyl group or a tetrahydropyrazinyl group. The compound (xxxv) having an xcex1-hydroxy nitrogen-containing aromatic heterocyclic group at the 5-position of the pyridine ring can be produced by hydrolyzing the xcex1-alkoxy nitrogen-containing aromatic heterocyclic compound (xxxiv). The solvent used in this reaction varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, an aqueous solution of a mineral acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or a mixed solvent of the above-mentioned aqueous solution of the mineral acid and acetic acid may be proposed. The reaction temperature is usually room temperature to 100xc2x0 C.
Production Process 12
In the formula, R2b, R4a, the ring A1 and the ring A2 have the same meanings as defined above; and R10 represents a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, etc. The compound (xxxvii) having an xcex1-hydroxy nitrogen-containing aromatic heterocyclic group at the 5-position of the pyridine ring can be produced by hydrolyzing the xcex1-alkoxy nitrogen-containing aromatic heterocyclic compound (xxxvi). The solvent used in this reaction varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, an aqueous solution of a mineral acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or a mixed solvent of the above-mentioned aqueous solution of the mineral acid and acetic acid may be proposed. The reaction temperature is usually room temperature to 100xc2x0 C.
Production Process 13
In the formula, R2c represents hydrogen atom, hydroxyl group, a C1-6 alkoxy group which may have a substituent group, a C1-6 alkyl group which may have a substituent group, a C6-14 aromatic hydrocarbon cyclic group which may have a substituent group or a 5- to 14-membered aromatic heterocyclic group which may have a substituent group; R3c represents a C6-14 aromatic hydrocarbon cyclic group which may have a substituent group or a 5- to 14-membered aromatic heterocyclic group which may have a substituent group; and R4a and X4 have the same meanings as defined above. The compound (xxviii) according to the present invention can be produced by reacting the 2-amino-5-halogenonicotinonitrile derivative (xxxix) with an aryl boron reagent or an aryl tin reagent in the presence of a palladium catalyst and a base in a solvent, to introduce an aromatic group into the 5-position of the pyridine ring in (xxxix). The palladium catalyst used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, dichlorobis(triphenylphoshine) palladium (II), palladium (II) acetate, tetrakis(triphenylphosphine) palladium (0), tris(dibenzylidene acetone) dipalladium (0), dichlorobis(acetonitrile) palladium (II) etc. may be proposed. The base used varies depending on the starting material, the solvent used, etc., and is not particularly limited so long as it is inert to the reaction. Preferably, an inorganic base such as potassium carbonate or calcium phosphate, or an organic amine such as ethyl diisopropyl amine may be proposed. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol or dimethyl ether, toluene, xylene, N,N-dimethylformamide, 1-methyl pyrrolidinone etc. may be proposed. The reaction temperature is usually room temperature to 150xc2x0 C.
Production Process 14
In the formula, R3d represents a C6-14 aromatic hydrocarbon cyclic group which may have a substituent group, a 5- to 14-membered aromatic heterocyclic group which may have a substituent group or a 5- to 14-membered non-aromatic heterocyclic group which may have a substituent group; and R2c and R4a have the same meanings as defined above. The compound (xli) according to the present invention can be produced by hydrolyzing the cyano group of the compound (xl) in the presence of a base in a solvent. The base used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, an inorganic base such as sodium hydroxide or potassium hydroxide may be proposed. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reacton and dissolves the starting material to a certain degree. Preferably, alcohols such as methanol or ethanol, or a mixture of such alcohols and water. The reaction temperature is usually room temperature to 150xc2x0 C.
Production Process 15
In the formula, R1b represents a carbamoyl group which may have a substituent group; and R2c, R3d and R4a have the same meanings as defined above. The carbamoyl derivative (xlii) according to the present invention can be produced by dehydrating condensation of the carboxylic acid derivative (xli) with an amine in the presence of a condensing agent in a solvent. As the condensing agent used, 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide etc. are preferred. The reaction is promoted by adding 1-hydroxybenzotriazole etc. When the amine to be condensed with the carboxylic acid has formed a salt with hydrogen chloride etc., a suitable amount of tertiary amine such as triethylamine is added. As the solvent used, for example, ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol, N,N-dimethylformamide, 1-methyl pyrrolidinone etc. are preferred. The reaction temperature is usually 0 to 50xc2x0 C., and more preferably around room temperature.
Production Process 16
In the formula, R2d represents hydrogen atom, a C1-6 alkoxy group which may have a substituent group, a C1-6 alkyl group which may have a substituent group, a C6-14 aromatic hydrocarbon cyclic group which may have a substituent group or a 5- to 14-membered aromatic heterocyclic group which may have a substituent group; the ring A3 represents pyridinyl group, pyrimidyl group or pyrazinyl group; R11 represents a C1-6 alkyl group which may have a substituent group, a C2-6 alkenyl group which may have a substituent group or a C2-6 alkynyl group which may have a substituent group; X5 represents an eliminating group such as a halogen atom or a sulfonate group which may have a substituent group; and R4a and ring A2 have the same meanings as defined above, respectively. The compounds (xliv) and (xlv) according to the present invention can be produced by reacting the compound (xliii) with R9xe2x80x94X5 in the presence of a base in a solvent. The base used varies depending on the starting material, the solvent used etc., and is not particularly limited so long as it is inert to the reaction. Preferably, inorganic bases represented by potassium carbonate, potassium bicarbonate and sodium carbonate may be proposed. The solvent generally used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it it inert to the reacton and dissolves the starting material to a certain degree. Preferably, an amide such as N,N-dimethylformamide may be proposed. The reaction temperature is preferably room temperature to 100xc2x0 C., and more preferably around 65xc2x0 C.
Production Process 17
In the formula, R12 represents a C6-14 aromatic hydrocarbon cyclic group which may have a substituent group or a 5- to 14-membered aromatic heterocyclic group which may have a substituent group; and R2c, R4a and ring A2 have the same meanings as defined above, respectively. The compound (xlvii) according to the present invention can be produced by reacting the compound (xlvi) with an aryl boron reagent in the presence of a base and a copper catalyst in a solvent. The base used in the reaction varies depending on the starting material, the solvent used etc., and is not particularly limited insofar as it is inert to the reaction. Preferably, a tertiary amine such as pyridine, diisopropyl ethylamine, triethylamine etc. may be proposed. The copper catalyst used varies depending on the starting material, the solvent used etc., and is not particularly limited insofar as it is inert to the reaction. Preferably, divalent copper such as copper acetate, copper bromide, copper sulfate etc. may be proposed, and copper acetate is more preferred. The solvent used varies depending on the starting material, reagents etc., and is not particularly limited insofar as it is inert to the reaction and dissolves the starting material to a certain degree. Preferably, N,N-dimethylformamide, tetrahydrofuran, ethyl acetate etc. may be proposed. The reaction temperature is preferably around room temperature.
The foregoing is a typical example of the method of producing the compound (I) according to the present invention, and the starting compound in production of the compound of the present invention may form a salt or a hydrate and is not particularly limited so long as it is inert to the reaction. Further, when the compound (I) according to the present invention is obtained in a free form, it can be converted into a salt which may be formed by the above-mentioned compound (I), in a usual manner. Further, the various resulting isomers (for example, geometric isomer, optical isomer based on asymmetric carbon, rotational isomer, stereoisomer and tautomer) of the compound (I) according to the present invention can be purified and isolated by using usual separating means, for example, re-crystallization, diastereomer salt method, enzyme fractionation method, and various kinds of chromatography (for example, thin layer chromatography, column chromatography and gas chromatography).
The compound represented by the above formula (I) according to the present invention, a salt thereof or a hydrate of them can be formed into a pharmaceutical preparation by a conventional method. As the preferable preparation forms, tablets, powders, fine granules, granules, coated tablets, capsules, syrups, troches, inhalations, suppositories, injections, ointments, eye ointments, eye drops, nose drops, ear drops, poultices, lotions etc. may be proposed. In pharmaceutical manufacturing, ordinarily used fillers, binders, disintegrating agents, lubricants, coloring agents, flavoring agents, and as necessary stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives and antioxidants may be used, and it may be prepared in a conventional method by blending ingredients generally used as starting materials for pharmaceutical preparations. As these ingredients, for example, (1) animal and vegetable oils such as soybean oil, tallow or synthetic glyceride; (2) hydrocarbons such as liquid paraffin, squalane or solid paraffin; (3) ester oils such as octyldodecyl myristate or isopropyl myristate; (4) higher alcohols such as cetostearyl alcohol or behenyl alcohol; (5) silicon resin; (6) silicon oil; (7) surfactants such as polyoxyethylene fatty ester, sorbitan fatty ester, glycerin fatty ester, polyoxyethylene sorbitan fatty ester, polyoxyethylene hydrogenated castor oil or polyoxyethylene-polyoxypropylene block copolymer; (8) water-soluble polymers such as hydroethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone or methyl cellulose; (9) lower alcohols such as ethanol or isopropanol; (10) polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol or sorbitol; (11) sugars such as glucose or sucrose; (12) inorganic powder such as silicic anhydride, aluminum magnesium silicate or aluminum silicate; and (13) pure water may be proposed. 1) As the fillers, for example, lactose, corn starch, white sugar, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide etc.; 2) as the binders, for example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, arabic gum, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene block polymer, megulumin, calcium citrate, dextrin, pectin etc.; 3) as the disintegrating agents, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, carboxymethyl cellulose calcium etc.; 4) as the lubricants, for example, magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil etc.; 5) as the coloring agents, any of which are approved to be added to pharmaceutical preparations; 6) as the flavoring agents, cocoa powder, menthol, aromatic powder, peppermint oil, borneol, cinnamon powder etc.; and 7) as the antioxidants, those which are approved to be added to pharmaceutical preparations, such as ascorbic acid, xcex1-tocopherol etc., maybe used, respectively.
1) The oral preparation is produced by mixing the compound according to the present invention or a salt thereof with fillers and if necessary with a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent etc., and then forming it in a usual manner into powders, fine granules, granules, tablets, coated tablets, capsules, etc. 2) The tablets and granules may be coated with a sugar or gelatin coating or if necessary with another suitable coating. 3) The liquid preparations such as syrups, injections and eye drops are prepared by mixing the active agent with a pH adjuster, a solubilizer and an isotonizing agent etc., and with a solubilizing aid, a stabilizer, a buffer, a suspension agent, an antioxidant etc. if necessary, followed by forming it into a preparation in a usual manner. The liquid preparation may be formed into a freeze-dried product and the injection can be administered intravenously, subcutaneously or intramuscularly. Preferable examples of the suspension agent include methyl cellulose, Polysorbate 80, hydroxyethyl cellulose, arabic gum, tragacanth powder, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate etc.; preferable examples of the solubilizing aid include polyoxyethylene hardened castor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate etc.; preferable examples of the stabilizer include sodium sulfite, sodium metasulfite, ether etc.; preferable examples of the preservative include methyl p-oxybenzoate, ethyl p-oxybenzoate, sorbic acid, phenol, cresol, chlorocresol etc. 4) The agent for external application can be produced in any conventional method. That is, the starting base material can make use of various starting materials ordinarily used in pharmaceutical preparations, quasi-drug, cosmetics, etc. For example, the material includes animal and vegetable oils, mineral oil, ester oil, waxes, higher alcohols, fatty acids, silicon oil, surfactants, phospholipids, alcohols, polyvalent alcohols, water-soluble polymers, clay minerals, pure water etc. If necessary, a pH adjuster, an antioxidant, a chelating agent, a preservative, a coloring agent, a perfume etc. can further be added. Further, ingredients having a differentiation-inducing action, a blood-stream promoting agent, a sterilizer, an antiinflammatory agent, a cell activator, vitamins, amino acids, a humectant, a keratin solubilizer etc. can also be incorporated as necessity.
Although the dose of the medicament according to the present invention varies depending on severeness of symptoms, age, sex, body weight, administration form, type of salt, chemical sensitivity, type of disease etc., it is given daily in one portion or in divided portions to an adult in a dose of usually about 30 xcexcg to 10 g, preferably 100 xcexcg to 5 g, more preferably 100 xcexcg to 100 mg for oral administration, or about 30 xcexcg to 1 g, preferably 100 xcexcg to 500 mg, more preferably 100 xcexcg to 30 mg for injection.
According to the present invention, a novel 2-aminopyridine compound could be provided. The compounds according to the present invention or a salt thereof have an excellent antagonistic action on an adenosine receptor (adenosine A1, A2a, A2b or A3 receptor), and are excellent as an antagonist for an adenosine A2 receptor, particularly for an adenosine A2B receptor. The compounds according to the present invention or a salt thereof are useful as an agent for treating or preventing a disease to which an adenosine receptor (adenosine A1, A2a, A2b or A3 receptor) relates, and a disease against which an antagonist for the receptor is efficacious. The compound according to the present invention or a salt thereof is useful not only as an agent for treating, preventing or improving constipation, irritable bowel syndrome, constipation accompanying irritable bowel syndrome, organic constipation, constipation accompanying enteroparalytic ileus, constipation accompanying congenital digestive tract dysfunction, constipation accompanying ileus, diabetes, diabetic complications, diabetic retinopathy, obesity, asthma etc., but also useful as a hypoglycemic agent, an improving agent for impaired glucose tolerance, a potentiating agent for insulin sensitivity, hypotensive agent, a diuretic, a therapeutic agent for osteoporosis, an anti-Parkinson""s disease agent, an anti-Alzheimer""s disease agent, a therapeutic agent for inflammatory intestinal diseases, a therapeutic agent for Crohn""s disease, etc.